The diagnosis of acute myocardial infarction may be made with the typical clinical findings of chest pain, coupled with sequential electrocardiographic changes. Biochemical laboratory tests relying on measurement of the release of creatine kinase (CK) or the CK-MB and CK-B myocardial injury and the size of the infarction. In many clinical cases the diagnosis can be made with good certainty. However, these traditional techniques are limited. Frequently it is not possible to determine whether an episode of ischemia has resulted in tissue damage.
The location and extent of damage to muscle in acute myocardial infarction are important determinants of patient prognosis. Determination of the infarct area is of clinical importance, especially with the development of newer therapeutic methods to limit infarct size.
D'Agostino first showed that calcium complexes will localize in necrotic myocardial cells. Am J. Pathol. 45:633 (1964). It is believed that phosphorus compounds such as pyrophosphate enter the damaged cell under anaerobic conditions to bind apatite-like calcium crystals. Tissue calcium in ischemically-injured myocardial cells increases in dense bodies within the mitochondria. Bonte et al first proposed that a pyrophosphate compound that would bind intracellular calcium could be used to image acute myocardial infarctions. Radiology 110: 473 (1974). Over ten years of experience with animal and clinical studies in man have confirmed the ability of technetium-99m labelled pyrophosphate to detect and size acute myocardial infarctions.
Animal studies have confirmed that technetium-99m labeled pyrophosphate localizes predominantly in areas of intact perfusion in the outer peripheral region of infarcts in tissue characterized by muscle cell calcification. Buja et al, J. Clin. Invest. 57: 1508-1522 (1976); Circulation 52: 546-607 (1975). This preferential localization in the border zone of an area of infarction permits better definition of the central area of necrosis in a pattern often described as the "donut" sign. Further studies have confirmed that pyrophosphate can also localize in peripheral ischemic, but not infarcted, myocardium. Bianco et al, J. Nucl Med. 24: 485-491 (1983). This ability to localize in the ischemic "area at risk" of infarction is a unique property of pyrophosphate which may be useful for evaluating newer drug interventions for limiting the infarct size.
The use of Tc-99m radiolabeled pyrophosphate has constituted an advance in the ability to detect and localize acute myocardial infarctions. However, the inherent low spatial resolution of nuclear medicine imaging devices limits this technique's usefulness particularly in diagnosing small subendocardial infarcts. Recent work has confirmed the need for better spatial resolution as the use of newer tomographic nuclear medicine cameras has resulted in improved diagnostic ability especially for small areas of infarction. In general, however, because of the limited spatial resolution of nuclear medicine imaging, it is not possible to separate the peri-infarct zone from the central area of necrosis, except in the cases of extremely large infarctions e.g., the "donut" sign.
Proton magnetic resonance imaging was first shown to be feasible by Lauterbur in 1973. The intensity of the radio frequency signals received from different tissues is affected by the distribution of protons in tissue and also by their relaxation times (T-1, T-2), which are in turn influenced by the local chemical environment and motion of molecules. Since water is the major constituent of most tissues, the magnetic resonance image intensity is largely controlled by the protons in water. Certain substances which are said to have paramagnetic properties can modify these relaxation times and change the appearance of the images.
Magnetic resonance imaging has been shown to be particularly suited for imaging of the cardiovascular system. Since rapidly flowing blood produces no magnetic resonance signal, there is a natural contrast between the blood and surrounding vascular and cardiac structures. By synchronizing the image acquisition to the electrocardiographic cycle (cardiac gating) the effects of cardiac motion can be minimized and high resolution images of the ventricular walls can be obtained. Lanzer et al., Radiology 150: 121 (1984); 155: 681-686 (1985).
Early studies performed in animal hearts ex situ without gating showed that acutely infarcted myocardium exhibit increased signal intensity relative to normal tissue. Direct measurements both in excised and bearing hearts have shown that the T-1 and T-2 relaxation times of acutely infarcted cardiac muscle are prolonged. This increase in T-1 and T-2 in infarcted muscle is a nonspecific finding related to a localized increase in tissue water from edema. Wesby et al, Circulation 69: 125 (1984); Frank et al, Clin Res. 17: 217A (1976) (abstract).
Following the early animal studies without ECG gating, additional studies demonstrated in man that acute myocardial infarction could be recognized as an area of increased magnetic resonance signal intensity with the use of ECG gating. Pohost et al., Circulation 66 (Supl II): II-39 (1982).
Most recently, studies have shown that the presence of a localized area of increased magnetic resonance signal intensity within the myocardium is not a specific finding for acute myocardial infarction, as this effect may be present in as many as 83% of asymptomatic normal volunteers. These recent studies have emphasized the need for a tissue-specific paramagnetic contrast agent which will localize only in areas of acute myocardial infarction.
Gd-DTPA (gadolinium ion chelated with the ligand diethylenetriaminepentaacetic acid) has been proposed as a paramagnetic contrast agent. Wesby et al., Radiology 153: 165-169 (1984); McNamara et al, Radiology 153: 157-163 (1984). This agent, which causes differential changes in T-1 and T-2 in tissues based upon differences in blood flow, has been shown to be helpful for identifying areas of infarct (no blood flow) from areas of intact perfusion. However, Gd-DTPA has no tissue specificity. It does not localize in the peri-infarction tissue.
While magnetic resonance imaging provides improved spatial resolution over nuclear imaging, there is presently no technique available for tissue-specific magnetic resonance imaging which would permit definition of an area of tissue calcification, in particular, the peri-infarct zone of an acute myocardial infarction. What is needed is a paramagnetic contrast agent which would permit precise localization and sizing of the infarct and peri-infarct zone.